Piyush M. Patel, MD, FRCPC

The main themes of the research being conducted in my laboratory are anesthetic neurotoxicity and CNS regeneration after ischemic and traumatic injury. In addition, our work is also applicable to the study of the mechanisms that underlie cognitive dysfunction in neurodegenerative diseases such as Alzheimer’s disease.

1) The traditional concept of general anesthesia is that anesthetics only produce a reversible suppression of the central nervous system without structurally altering the CNS. Recent data indicate, however, that exposure of the developing brain to anesthetics during the period of synaptogenesis leads to neuronal apoptosis. Moreover, animals exposed during the neonatal period to anesthesia manifest cognitive dysfunction upon reaching adulthood. Our work shows clearly that anesthetic neurotoxicity is in part mediated by preferential signaling of proBDNF via the p75NTR. The downstream effect of this is RhoA activation, actin depolymerization and collapse of neuronal growth cones. This leads to a substantial reduction in neurite outgrowth, loss of synapses and neuronal apoptosis. We have developed a therapeutic approach wherein inhibition of RhoA activation prevents anesthetic neurotoxicity. Ongoing work in this area will detail the extent of toxicity, its impact on the development of neuronal networks and long term alterations in memory and learning performance.

2) Despite intensive investigative effort focused on the regeneration of neurons after ischemia and traumatic brain and spinal cord injury, advances in CNS regeneration have been limited. Research in this field has focused on removal of growth inhibition, stem cell transplantation and enhancement of the intrinsic growth potential of neurons. Our research deals with the latter approach. Exciting preliminary data from our laboratory show that upregulation of the membrane raft protein caveolin-1, which scaffolds a number of receptors and signaling molecules, results in the upregulation of a multitude of receptors and their associated signaling molecules that significantly enhance neuronal growth. In ongoing research in the laboratory, we are devising novel viral vectors by which caveolin-1 expression can be increased in neurons in the brain. The intention is to increase the tolerance of neurons against ischemic injury and to enhance their growth potential for axonal sprouting in the post injury setting.

The methodology that we employ in the laboratory include in vitro models of cell culture, ischemia injury, molecular biology and imaging techniques (confocal and deconvolution microscopy). In vivo, we utilize models of traumatic brain injury (controlled cortical impact), both focal and global ischemia, direct injection of viral vectors into specific regions of the brain, injury evaluation (molecular biology, imaging) and evaluation of behavioral outcome (water maze, Barnes maze, fear conditioning). We utilize motor and sensory evoked potential to assess the impact of injury and the effect of our interventions on functional recovery. In addition, we are in the process of developing electrophysiology to study single neuron function. In aggregate, trainees gain familiarity with a wide variety of research techniques that range from in vitro cell systems to in vivo injury models to cognitive and behavioral analysis. This is of vital importance in translational research. See website: http://rppresearchgroups.ucsd.edu